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\begin{document}

\title{Rare Congenital Dyserythropoietic Anemia of Childhood: A Case report}



\author[1]{Hamzeh   Al Hussien}%
\author[1]{Basil  Al-Ekeer }%
\author[2]{Hashem  Abu Serhan}%
\author[1]{Issam  Haddadin}%
\author[2]{Abdulqadir Nashwan}%
\affil[1]{Islamic Hospital}%
\affil[2]{Hamad Medical Corporation}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Congenital dyserythropoietic anemias (CDA) is a heterogeneous class of
anemia of varying degrees of ineffective erythropoiesis and secondary
hemochromatosis. We reported a case of CDA and showed our approach to
reaching a diagnosis, highlighting the importance of the typical
morphological appearance of bone marrow erythroblasts to reach the
diagnosis.%
\end{abstract}%



\sloppy


\textbf{Rare Congenital Dyserythropoietic Anemia of Childhood: A Case
report}

Hamzeh F. Al Hussien\textsuperscript{1}, Basil N.
Al-Ekeer\textsuperscript{1}, Hashem Abu Serhan\textsuperscript{2}, Issam
Haddadin\textsuperscript{1}, Abdulqadir J. Nashwan\textsuperscript{3*}

\begin{enumerate}
\tightlist
\item
  Department of Pediatrics, Islamic Hospital, Amman, Jordan
\item
  Department of Ophthalmology, Hamad Medical Corporation, Doha, Qatar
\item
  Department of Nursing, Hamad Medical Corporation, Doha, Qatar
\end{enumerate}

*Corresponding author:

Abdulqadir J. Nashwan

anashwan@hamad.qa

Tel: (+974) 40240487

Mob: (+974) 66473549

P.O. Box 3050

Hamad Medical Corporation, Doha, Qatar

ORCID: https://orcid.org/0000-0003-4845-4119

\textbf{Informed Consent}

Written informed consent was obtained from the patient's legal guardian
to publish this report in accordance with the journal's patient consent
policy.

\textbf{Abstract}

Congenital dyserythropoietic anemias (CDA) is a heterogeneous class of
anemia of varying degrees of ineffective erythropoiesis and secondary
hemochromatosis. We reported a case of CDA and showed our approach to
reaching a diagnosis, highlighting the importance of the typical
morphological appearance of bone marrow erythroblasts to reach the
diagnosis.

\textbf{Key Clinical Message}

To avoid delay in diagnosing CDA and provide early care and better
management, we urge clinicians to have a high degree of suspicion for
congenital anemias when there is evidence of ineffective erythropoiesis
in a child.

\textbf{Keywords:} anemia; pediatrics; bone marrow; erythropoiesis; case
report

\textbf{Introduction}

Congenital dyserythropoietic anemia (CDA) is an uncommon hematological
condition reported primarily in Central and Western Europe and North
Africa {[}1-3{]}. The hallmark of the disease is ineffective
erythropoiesis as the main feature, and there are distinct morphological
abnormalities of the bone marrow's erythroblasts. Therefore, it should
be considered in any patient with chronic anemia. It is divided into
three categories (CDA I, CDA II, and CDA III), with the most common type
II and CDA III, whose nonfamilial type is the rarest. A majority of CDA
cases are autosomal recessive in nature {[}4{]}. In our case, we showed
the way we used to reach our diagnosis and that the typical
morphological appearance of bone marrow erythroblasts is considered the
cornerstone of the diagnosis. Still, a blood smear might give us a hint.

\textbf{Case Presentation}

A 6-year-old female patient presented with chronic anemia for
evaluation. She was doing well until the age of 3 years when the mother
started to notice gradual and progressive pallor. It was associated with
lethargy and intolerance to exercise with attacks of palpitation. Since
then, the patient has been treated as a case of hemolytic anemia with
regular blood transfusion every 3 months.

The patient is the product of vaginal delivery, term, and no NICU
admission. The patient had two previous admissions for chest infections
before the age of 3 years. The patient had DDH.

The parents are consanguineous (first-degree). The patient has one
younger healthy sister. No family history of chronic illnesses or
splenectomy.

On examination, the patient had frontal bossing and mild maxillary
hypertrophy with depression of the nasal bridge. The spleen was felt 6
cm below the costal margin.

Peripheral blood film showed normochromic macrocytic RBCs, marked
polychromasia and binucleated erythroid, mild poikilocytosis (ovalocyte,
teardrop, microspherocyte), few atypical lymphocytes with normal
platelets (\textbf{Fig. 1)} .

Bone marrow smears showed distinct hypercellularity due to erythroid
hyperplasia \textbf{(Fig.3)} . The myeloid/erythroid ratio was 6:1, and
the erythroid precursors were quantitatively markedly increased; also,
erythroid maturation was megaloblastic and dyserythropoietic with many
binucleated forms \textbf{(Fig.2)} . Blasts was not increased, and there
was no evidence of fibrosis.

These findings of bone marrow aspirate and laboratory results fit the
diagnosis of congenital dyserythropoietic anemia type II.

\textbf{Discussion}

An uncommon hematological condition known as congenital
dyserythropoietic anemia (CDA) has primarily been documented in Central
and Western Europe and North Africa {[}1, 3{]}. The hallmark of the
disease is ineffective erythropoiesis as the main feature, and there are
distinct morphological abnormalities of the bone marrow's erythroblasts.
It should be considered in any patient with chronic anemia. It is
classified into three types (CDA I, CDA II, and CDA III), with the most
common being type II and CDA III and its nonfamilial type being the
rarest. A majority of CDA cases are autosomal recessive in nature.
{[}4{]}.

To reach the precise diagnosis of congenital anemias is often delayed.
Congenital anemia, jaundice, or hereditary evidence are necessary for
diagnosing CDAs. Also, evidence of ineffective erythropoiesis should be
present. In addition, the erythroblasts' characteristic morphology is
thought to be the key to making the diagnosis, and it is important to
rule out congenital anemias, including thalassemia syndromes,
hemoglobinopathies, and hereditary sideroblastic anemias. Ineffective
erythropoiesis should be suspected if there is inadequate
reticulocytosis to the degree of anemia despite erythroid hyperplasia;
indirect hyperbilirubinemia and low haptoglobin indicates ongoing
intramedullary and extramedullary hemolysis {[}4{]}.

Moreover, if appropriate preparation techniques are applicable in bone
marrow aspirate, hypercellularity and distinct erythropoietic
hyperplasia is always seen in histobiopsies. By morphological study
using light microscopy, CDA I can be diagnosed with great specificity.
The most specific finding is the abnormality of chromatin structure with
fine chromatin bridges. However, the most specific finding in CDA II is
the existence of binucleated cells with two equal-sized nuclei in each
cell. Pseudo-Gaucher cells that contain birefringent needles can be seen
in types I and II {[}2{]}. Furthermore, iron loading and cholelithiasis
are found in all forms of CDA {[}4{]}. Peripheral blood smear in most
cases of CDA shows anisopoikilocytosis, mature erythroblasts, basophilic
stippling, and poikilocytes {[}2{]}.

Differential CDA diagnoses include thalassemia syndromes, some
hemoglobinopathies, hereditary sideroblastic anemia, congenital
myelodysplasia, and congenital anemia such as Blackfan-Diamond anemia
and Fanconi anemia. Also, other forms of CDA should be taken into
account {[}1{]}. Our patient has chronic anemia with chronic blood
transfusion. Also, she has splenomegaly with features of extramedullary
hematopoiesis. Moreover, a blood smear showed normochromic macrocytic
RBCs with mild poikilocytosis and anisopoikilocytosis. The binucleated
erythroid was found even in the peripheral blood, there was
reticulocytosis with a negative direct coombs test. These laboratory
results are commonly not observed in hemoglobinopathies or thalassemia
syndromes. Hereditary sideroblastic anemia was ruled out because neither
ringed sideroblasts nor dysplastic characteristics on the
granulocytic/megakaryocytic lineage were discovered. Bone marrow
aspirate showed hypercellularity, with the erythroid precursors
quantitatively markedly increased; also, erythroid maturation was
megaloblastic and dyserythropoietic with many binucleated forms. Blasts
were not increased, and there was no evidence of fibrosis. These
findings of bone marrow aspirate and laboratory results fit the
diagnosis of congenital dyserythropoietic anemia type II.

In conclusion, any kid with chronic anemia, hepatosplenomegaly, evidence
of extramedullary hematopoiesis, and characteristics of erythroid
hyperplasia and dyserythropoiesis in bone marrow aspirate studies should
be evaluated for congenital dyserythropoietic anemia. The diagnosis can
be made with high accuracy using bone marrow aspirate analysis and
peripheral blood smear analysis.

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

The article describes a case report. Therefore, no additional permission
from our Ethics Committee was required.

\textbf{Availability of data and material}

All data generated or analyzed during this study are included in this
published article.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

This study was not funded.

\textbf{Authors' contributions}

Hamzeh F. Al Hussien, Basil N. Al-Ekeer, Hashem Abu Serhan, Issam
Haddadin, Abdulqadir J. Nashwan: Data Collection, Literature Search,
Manuscript Preparation

All authors read and approved the final manuscript

\textbf{Acknowledgments}

Open Access funding provided by the Qatar National Library.

\textbf{References}

1. Kato K et al (2001) Congenital dyserythropoietic anemia type 1 with
fetal onset of severe anemia. J Pediatr Hematol Oncol

23(1):63--66

2. Heimpel H, Kellermann K, Neuschwander N, Hogel J, Schwarz K (2010)
The morphological diagnosis of congenital dyserythropoietic anemia:
results of a quantitative analysis of peripheral blood and bone marrow
cells. Haematologica 95(6):1034--1036

3. Heimpel H et al (2006) Congenital dyserythropoietic anemia type I
(CDA I): molecular genetics, clinical appearance, and prognosis based on
long-term observation. Blood 107:334--340

4. Heimpel H (2004) Congenital dyserythropoietic anemias: epidemiology,
clinical significance, and progress in understanding their pathogenesis.
Ann Hematol 83:613--621

\textbf{Figure Legends}

\textbf{Fig. 1} Peripheral blood smear, poikilocytosis, polychromasia,
binucleated erythroid (leishman stain 400X).

\textbf{Fig. 2} Bone marrow aspirate from our patient, erythroid
hypercellularity and binucleated forms (leishman stain 400X).

\textbf{Fig. 3} Bone marrow biopsy, from our patient showing erythroid
hypercellularity (H\&E stain 400X).\selectlanguage{english}
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